Bottom Line:
Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability.We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction.In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

ABSTRACTThe identification of endothelial progenitor cells (EPCs) has led to a significant paradigm in the field of vascular biology and opened a door to the development of new therapeutic approaches. Based on the current evidence, it appears that EPCs may make both direct contribution to neovascularization and indirectly promote the angiogenic function of local endothelial cells via secretion of angiogenic factors. This concept of arterial wall repair mediated by bone marrow (BM)-derived EPCs provided an alternative to the local "response to injury hypothesis" for development of atherosclerotic inflammation. Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability. EPCs function may also be highly dependent on a well-controlled oxidant stress because EPCs NO bioavailability (which is highly sensitive to oxidant stress) is critical for their in vivo function. The critical question is whether oxidant damage directly leads to an impairment in EPCs function. It was revealed that activation of angiotensin II (Ang II) type 1 receptor stimulates nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the vascular endothelium and leads to production of reactive oxygen species. We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction. Consistently, both Ang II receptor 1 blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors have been reported to increase the number of EPCs in patients with cardiovascular disease. In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

Figure 1: Hemangioblast, originated from hematopoietic cell, is resident in bone marrow niches, in a quiescent state. The stimulation by circulating cytokines induces the activation of matrix metalloproteinase-9 (MMP-9) through an Akt, nitric oxide dependent pathway. MMP-9 promotes the transformation of membrane bound Kit-ligand to a soluble Kit-ligand. This activation is followed by detachment of early c-Kit+ progenitor cells from the bone marrow stromal niche and their subsequent movement to the vascular zone of the bone marrow. An important regulation is VEGF and SDF-1, which binds to its receptor VEGFR-2 and CXCR4, respectively, thus mediating further maturation of the cascade hemangioblast-angioblast-early endothelial progenitor cells (EPC)-late EPCs. Bone marrow-derived EPCs are of hematopoietic origin and possibly derive from the hemangioblast. These early progenitors (CD133+/CD34+/VEGFR-2+/CD14-) represent a small population with proliferative potential, capable to give rise to late endothelial outgrowth. Cells of myeloid origin (CD14+) may also trans-differentiate into endothelial cells and secret angiogenic factors, but their proliferative potential is limited and they did not generate a stable late outgrowth.

Mentions:
Recruitment of EPCs from the BM quiescent niche has been found to be associated with the activation of proteinases such as elastase, cathepsin G, and matrix metalloproteinases (MMPs) [40]. These enzymes proteolytically cleave the extracellular matrix- or cell membrane-bound molecules responsible for EPCs’ adhesive bonds on BM stromal cells (Fig. (1)). These cells express membrane-bound Kit ligand (mKitL), which binds to the EPCs membrane receptor c-kit when the ligand is in its soluble form (sKitL). MMP-9 proteolytically cleaves mKitL to sKitL, which then interacts with the EPCs c-kit receptor to conduct the signal essential for BM-EPCs differentiation and migration to the peripheral blood (PB) [41] (Fig. (1)). One of the models used in studying the recruitment of BM hematopoietic EPCs use BM cell suppression by cytotoxic agents. This suppression does not affect hematopoietic stem cells in the Go phase of the cell cycle. Therefore, these cells may serve as a cell population to reconstitute hematopoiesis and EPCs release. The introduction of cytotoxic suppression in the BM of MMP-9+/+ and MMP-9-/- mice resulted in poor recruitment and differentiation of hematopoietic cells only in the latter group of animals [40]. Treatment of MMP-9+/+ mice with VEGF, stromal-derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) caused a marked increase in the concentration of plasma sKitL compared with untreated animals [40]. The results of this experiment proved that VEGF, SDF-1, and G-CSF play significant roles in the induction of MMP-9 precursor biosynthesis, secretion, and further mobilization of BM-EPCs to the PB [41-44] (Fig. (1)).

Figure 1: Hemangioblast, originated from hematopoietic cell, is resident in bone marrow niches, in a quiescent state. The stimulation by circulating cytokines induces the activation of matrix metalloproteinase-9 (MMP-9) through an Akt, nitric oxide dependent pathway. MMP-9 promotes the transformation of membrane bound Kit-ligand to a soluble Kit-ligand. This activation is followed by detachment of early c-Kit+ progenitor cells from the bone marrow stromal niche and their subsequent movement to the vascular zone of the bone marrow. An important regulation is VEGF and SDF-1, which binds to its receptor VEGFR-2 and CXCR4, respectively, thus mediating further maturation of the cascade hemangioblast-angioblast-early endothelial progenitor cells (EPC)-late EPCs. Bone marrow-derived EPCs are of hematopoietic origin and possibly derive from the hemangioblast. These early progenitors (CD133+/CD34+/VEGFR-2+/CD14-) represent a small population with proliferative potential, capable to give rise to late endothelial outgrowth. Cells of myeloid origin (CD14+) may also trans-differentiate into endothelial cells and secret angiogenic factors, but their proliferative potential is limited and they did not generate a stable late outgrowth.

Mentions:
Recruitment of EPCs from the BM quiescent niche has been found to be associated with the activation of proteinases such as elastase, cathepsin G, and matrix metalloproteinases (MMPs) [40]. These enzymes proteolytically cleave the extracellular matrix- or cell membrane-bound molecules responsible for EPCs’ adhesive bonds on BM stromal cells (Fig. (1)). These cells express membrane-bound Kit ligand (mKitL), which binds to the EPCs membrane receptor c-kit when the ligand is in its soluble form (sKitL). MMP-9 proteolytically cleaves mKitL to sKitL, which then interacts with the EPCs c-kit receptor to conduct the signal essential for BM-EPCs differentiation and migration to the peripheral blood (PB) [41] (Fig. (1)). One of the models used in studying the recruitment of BM hematopoietic EPCs use BM cell suppression by cytotoxic agents. This suppression does not affect hematopoietic stem cells in the Go phase of the cell cycle. Therefore, these cells may serve as a cell population to reconstitute hematopoiesis and EPCs release. The introduction of cytotoxic suppression in the BM of MMP-9+/+ and MMP-9-/- mice resulted in poor recruitment and differentiation of hematopoietic cells only in the latter group of animals [40]. Treatment of MMP-9+/+ mice with VEGF, stromal-derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) caused a marked increase in the concentration of plasma sKitL compared with untreated animals [40]. The results of this experiment proved that VEGF, SDF-1, and G-CSF play significant roles in the induction of MMP-9 precursor biosynthesis, secretion, and further mobilization of BM-EPCs to the PB [41-44] (Fig. (1)).

Bottom Line:
Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability.We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction.In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

ABSTRACTThe identification of endothelial progenitor cells (EPCs) has led to a significant paradigm in the field of vascular biology and opened a door to the development of new therapeutic approaches. Based on the current evidence, it appears that EPCs may make both direct contribution to neovascularization and indirectly promote the angiogenic function of local endothelial cells via secretion of angiogenic factors. This concept of arterial wall repair mediated by bone marrow (BM)-derived EPCs provided an alternative to the local "response to injury hypothesis" for development of atherosclerotic inflammation. Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability. EPCs function may also be highly dependent on a well-controlled oxidant stress because EPCs NO bioavailability (which is highly sensitive to oxidant stress) is critical for their in vivo function. The critical question is whether oxidant damage directly leads to an impairment in EPCs function. It was revealed that activation of angiotensin II (Ang II) type 1 receptor stimulates nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the vascular endothelium and leads to production of reactive oxygen species. We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction. Consistently, both Ang II receptor 1 blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors have been reported to increase the number of EPCs in patients with cardiovascular disease. In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.